This project is designed to study the morphology and pathogenesis of demyelination in mouse central nervous system (CNS) compared to the peripheral nervous system (PNS) after corneal inoculation of herpes simplex Type I virus (HSV). The experimental model to be used produces demyelination associated with a mononuclear response in the CNS 4-7 days after corneal infection with HSV. Immunosuppression and preliminary work with Nude (athymic) mice demonstrates that with reduction of the cellular infiltration on days 7-9 there is a marked reduction in the amount of CNS demyelination. Recent studies of the lesions 60-70 hours post infection demonstrate astrocytic infection and cell lysis with a perivascular mononuclear cell infiltrate. Does early astrocytic cell lysis release viral antigens which attract nonspecific mononuclear cells? Would extracellular virus in the PNS create a demyelinative lesion? Does the early nonspecific cellular infiltrate initiate demyelination? Are these cells then responsible for recruiting the mononuclear cells present at day 7-9 post infection? Are the cells by day 7 immunespecific T cells directed against HSV? 1) Peroxidase labeling of viral antigen in the early lesion at the electron microscopic level will assess the role of virus in CNS vs. PNS. The effects of microinjection of live virus into extracellular spaces of the sciatic nerve will be evaluated morphologically. 2) Macrophage depletion studies in Swiss mice followed by HSV infection will evaluate the role of the early mononuclear cell response. To further assess nonspecific macrophages, the early lesion in Nude mice will be contrasted to the same process in immune competent litter mates. Perhaps both groups develop an initial lesion with nonspecific cells but only the immune competent animals with T cells can produce significant demyelination. 3) To characterize the specificity of the T cell response, myelinating tissue cultures of PNS and CNS will be exposed to T cells sensitized to HSV. Immunological reconstitution of immunosuppressed infected animals with T cells sensitized to HSV will determine whether these cells can reproduce the lesion.